1. Field of the Invention
This invention relates to a method of stabilizing acetylsalicylic acid compositions. More particularly, it relates to a stabilized acetylsalicylic acid composition with dimethyl isosorbide.
2. Description of the Prior Art
Aspirin, which exhibits a unique combination of effects on anti-inflammatory antipyretic, and analgesic treatments, is perhaps the most popular and effective non-prescription analgesic drug. However, it has been cautioned that aspirin ingestion can cause severe gastrointestinal bleeding in users and particularly, in patients with gastrointestinal lesions (P. R. Holt, Proc. Soc. Exp. Biol. Med., 102, 517 (1959); P. H. N. Wood, S. E. A. Harvey, and A. Dixon, Brit, Med. J., 1, 669 (1962); M. I. Grossman, K. K. Matsumote, and R. J. Lichter, Gastroenterology, 40, 383 (1961)). Although the mechanism by which the blood is lost is still unclear, studies (J. R. Leonards and G. Levy, J. Pharm. Sci., 58, 1277 (1969); and A. Weiss, E. R. Pitman, and E. C. Graham, Amer. J. Med., 31, 266 (1961)), have shown that aspirin, when given orally in a liquid form or when given intravenously, produces no occult bleeding. On the other hand, aspirin tablets are found to cause gastric bleeding particularly when tablets disintegrate slowly and remain in the stomach as large tablet fragments. These results suggest that the gastric irritation by aspirin may be greatly reduced by reducing the particle size of the drug. The reduction of the drug particle size in the gastrointestinal fluid may be best achieved by using a liquid dosage form. Hence, many attempts have been made to formulate a stable aspirin solution to reduce the undesirable side effect (H. R. Mehta and F. G. Drommond, J. Amer. Phar. Assoc. Pract. Ed., 15, 103 (1954); H. W. Tomski and L. S.Waller, Pharm. J., 144, 53 (1940); M. Farges, U.S. Pat. No. 3,316,150, Feb. 26, 1964; L. A. Luzzi, C. W. Whitworth, and H. W. Jun, J. Pharm. Sci., 62, 1184 (1973); and T. W. Schwarz, N. G. Shvemar, and R. G. Renaldi, J. Amer. Pharm. Assoc. Pract. Ed., 19, 40 (1958)).
The preparation of a stable liquid formulation of aspirin has become a classical pharmaceutical problem because of the instability of aspirin in various solvents. In aqueous solutions or in solvents containing water moisture, aspirin is notoriously unstable. The degradation has been known to be due to the hydrolysis of aspirin into salicylic acid and acetic acid. Studies (L. J. Edward, Trans. Faraday Soc., 46, 723 (1956), also Trans. Faraday Soc., 48, 696 (1952)), show that the hydrolysis follows first order kinetics and is subject to acid and base catalysis. Because of the rapid hydrolysis of aspirin in aqueous media, the attempts of liquid formulation of aspirin have been limited to the use of some non-aqueous solvents such as propylene glycol (H. R. Mehta and F. G. Drommond, J. Amer. Pharm. Assoc. Pract. Ed., 15, 103 (1954)), ethyl alcohol (H. W. Tomski and L. S. Waller, Pharm. J., 144, 53 (1940)), glycerol (M. Farges, U.S. Pat. No. 3,316,150, Feb. 26, 1964, and polyethylene glycol (T. W. Schwarz, N. G. Shvemar, and R. G. Renaldi, J. Amer. Pharm. Assoc. Pract. Ed., 19, 40 (1958)). However, in addition to the solubility and hydrolysis (due to traces of moisture) problems that may be inherited in the use of these solvents, the formulations may also have to confront with another form of aspirin degradation as suggested by the study of Jun et al (H. W. Jun, C. W. Whitworth, and L. A. Luzzi, J. Pharm. Sci., 61, (1972)). In this study, it was reported that aspirin undergoes trans-esterification with polyethylene glycol-400 to form salicylic acid and acetylated polyethylene glycol under prolonged storage. Although similar reactions have not been reported for the other hydroxyl solvents, it does not preclude the possibility of aspirin degradation via trans-esterification under long term storage. To circumvent the aspirin degradation, Luzzi and co-workers (L. A. Luzzi, C. W. Whitworth, and H. W. Jun, U.S. Pat. No. 3,842,170, Oct. 15, 1974) have proposed the use of esterified polyethylene glycol in the liquid formulation of aspirin.
In the past, attempts have been made to solubilize acetylsalicylic acid or to convert it to a fluid form in order to render acetylsalicylic acid compositions more palatable. This is particularly important for those people who find it difficult to consume tablets containing acetylsalicylic acid. Also, the administration of acetylsalicylic acid in pediatric practice is often difficult when tablets have to be sectioned in halves or quarters in order to provide the proper dosage of the drug for children. Thus, a need has existed for fluid compositions of acetylsalicylic acid for the accurate and convenient administration of the drug.
It has been known that in various pharmaceutical dosage forms, especially the liquid dosage forms, acetylsalicylic acid undergoes decomposition in the presence of water, aqueous or monohydroxy alcoholic solutions to salicylic acid and acetic acid. Several attempts have been made to formulate stable fluid solutions or suspensions of acetylsalicylic acid in a solvent mixture of high proof ethyl alcohol and high test anhydrous glycerin (U.S. Pat. No. 1,787,924) and in glycerin and propylene glycol solvents (U.S. Pat. No. 3,316,150 and British Pat. No. 1,147,348). In addition, polyethylene glycol suppository bases have been formulated which may contain acetylsalicylic acid or other medicinal agents (U.S. Pat. No. 2,975,099). However, it has been found that significant decomposition of acetylsalicylic acid still occurs in polyhydric alcohol bases despite the apparent absense of water. This factor is not as important as the hydrolytic effect water has on acetylsalicylic acid, but it is a significant factor when the "shelf-life" of anhydrous polyhydric alcohol-acetylsalicylic acid compositions is involved. The prior art has sought a solution to the problem of deterioration of acetylsalicylic acid by forming compositions of acid in polyhydric alcohol bases, but these attempts have only been partially successful. It has been shown that the decomposition of acetylsalicylic acid in apparently anhydrous polyhydric alcohols occurs via a transesterification reaction in which salicylic acid and acetylated polyhydric alcohol are produced. Specifically, the decomposition of acetylsalicylic acid has been shown to occur via a transesterification reaction with a polyethylene glycol base to produce salicylic acid and polyethylene glycol acetate. To circumvent this problem, (U.S. Pat. No. 3,842,170) esterified polyethylene glycol has been used in the liquid formulation of aspirin, however, this has not proved to be effective as problems with toxicity and pernicious, unpleasant taste has been noted.
Dimethyl isosorbide has been used as a solvent carrier for various pharmaceuticals, e.g., (U.S. Pat. No. 3,699,230) muscle relaxing drugs, wherein an additive synergistic effect has been noted, and (U.S. Pat. No. 4,082,881) various steroids when used in the form of an ointment, cream, lotion or parenteral liquid, such as eye drops, etc.
A need, therefore exists for acetylsalicylic compositions in which decomposition of the acid by hydrolysis and by transesterification is avoided. In particular, a need exists for fluid compositions of acetylsalicylic acid which are stable to decomposition via hydrolysis and transesterification.